Toxaphene inhibition of calmodulin-dependent calcium ATPase activity in rat brain synaptosomes

Effect of toxaphene on Ca2+-ATPase activity in rat brain synaptosomes was studied in vitro and in vivo. Ca2+-ATPase in calmodulin-depleted synaptosomes was inhibited in vitro to a maximum of about 50% at 150 microM toxaphene. Substrate activation kinetics of Ca2+-ATPase in synaptosomes revealed that toxaphene inhibited the enzyme activity noncompetitively by decreasing Vmax values, without affecting the enzyme-substrate affinity. Toxaphene inhibited the calmodulin activated Ca2+-ATPase activity in a concentration-dependent manner with an IC50 of 10 microM, a concentration at which no significant effect was observed on basal enzyme activity. Nuclear and P2 fraction (synaptosomes) calmodulin levels were reduced significantly in toxaphene-treated rats. The synaptosomal Ca2+-ATPase was also reduced to about 45% in toxaphene-treated rats and the activity was restored to normal levels by the exogenously added calmodulin. These results suggest that toxaphene may cause synaptic dysfunction by interfering with calmodulin and its regulation of neuronal calcium.